(a) Field of the Invention
The invention relates to agents having potent antifibrillogenic activity for the treatment of amyloidosis disorders and for imaging of amyloid deposits. These agents include peptides and peptidomimetic compounds thereof.
(b) Description of Prior Art
Amyloidosis refers to a pathological condition characterized by the presence of amyloid fibers. Amyloid is a generic term referring to a group of diverse but specific extracellular protein deposits that are seen in a number of different diseases. Though diverse in their occurrence, all amyloid deposits share common morphologic properties, stain with specific dyes (e.g. Congo red), and have a characteristic red-green birefringent appearance in polarized light after staining. They also share common ultrastructural, x-ray diffraction and infrared spectra features.
Some amyloidotic diseases can be idiopathic but most of these diseases appear as a complication of a previously existing disorder. For example, primary amyloidosis can appear without any other pathology or can follow plasma cell dyscrasia or multiple myeloma. Secondary amyloidosis is usually seen associated with chronic infection (such as tuberculosis) or chronic inflammation (such as rheumatoid arthritis). A familial form of secondary amyloidosis is also seen in Familial Mediterranean Fever (FMF). This familial type of amyloidosis, as one of the other types of familial amyloidosis, is genetically inherited and is found in specific population groups. Isolated forms of amyloidosis are those that tend to involve a single organ system. Different amyloids are also characterized by the type of protein present in the deposit. For example, neurodegenerative diseases such as scrapie, bovine spongiform encephalitis, Creutzfeldt-Jakob disease and the like are characterized by the appearance and accumulation of a protease-resistant form of a prion protein (referred to as AScr or PrP-27) in the central nervous system. Similarly, Alzheimer's disease, another neurodegenerative disorder, is characterized by congophilic cerebral angiopathy, neuritic plaques and neurofibrillary tangles. In this case, the plaque and blood vessel amyloid is formed by the deposition of fibrillar Aβ amyloid protein. In adult-onset diabetes, amyloids containing the IAPP amyloid protein accumulate in the pancreas. Other systemic diseases, complications of long-term hemodialysis and sequelae of long-standing inflammation or plasma cell dyscrasias are characterized by the accumulation of amyloids systemically. In each of these cases, a different amyloidogenic protein is involved in amyloid deposition.
Once these amyloids have formed, there is no known, widely accepted therapy or treatment that significantly dissolves the deposits in situ.
Each amyloidogenic protein has the ability to organize into β-sheet and to form insoluble fibrils that get deposited extracellularly. Each amyloidogenic protein, although different in amino acid sequence has the same property of forming fibrils and binding to other elements such as proteoglycan (glycosaminoglycan), amyloid P and complement component. Moreover, each amyloidogenic protein has amino acid sequences which, although different, will show similarities such as regions with the ability to bind to GAG's (referred to as the GAG binding site) as well as other regions which will promote β-sheet formation referred to as β-sheet region.
In specific cases, amyloidotic fibrils once deposited can become toxic to the surrounding cells. As per example, the Aβ fibrils organized as senile plaques have been shown to be associated with dead neuronal cells and microgliosis in patients with Alzheimer's disease. When tested in vitro, Aβ peptide was shown to be capable of triggering an activation process of the microglia (brain macrophages), which would explain the presence of microgliosis and brain inflammation found in the brain of patients with Alzheimer's disease.
In another type of amyloidosis seen in patients with Type II diabetes, the islet amyloidogenic protein, IAPP, has been shown to induce β-islet cell toxicity in vitro. Hence, appearance of IAPP fibrils in the pancreas of Type II diabetic patients could contribute to the loss of the β islet cells (Langerhans) and organ dysfunction.
Particularly, in patients with Alzheimer's Disease, an agent capable 1) of preventing amyloid fibril formation and deposition and 2) of directly or indirectly inhibiting Aβ-induced neurotoxicity and inflammation (microgliosis), could be a treatment of choice to prevent and arrest the development of Alzheimer's disease.
WO-A-9808868 concerns compounds that modulate natural beta-amyloid peptide aggregation. The compounds comprise a peptide, preferably based on a beta-amyloid peptide, that is comprised of 3–5 D-amino acid residues and includes at least two D-amino acid residues independently selected from the group consisting of D-leucine, D-phenylalanine and D-valine. In one embodiment the peptide is a retro-inverso isomer of a beta-amyloid peptide. In certain embodiments, the peptide is modified at the amino-terminus, the carboxy-terminus, or both.
It would be highly desirable to be provided with agents having potent antifibrillogenic activity for the treatment of amyloidosis disorders.